The goal of this project is to map the fate of tubular epithelial cells in the kidney and genitourinary(GU) tract of the mouse during normal embryonic development and following tubular injury. Ksp-cadherin is a unique tissue-specific gene whose expression is restricted to tubular epithelial cells in the kidney and developing GU tract. Recently, transgenic mice have been produced in which the Ksp-cadherin gene promoter directs the expression of green fluorescent protein (GFP) and Cre recombinase exclusively in tubular epithelial cells of the mesonephros, metanephros, ureteric bud, and Wolffian and Mtillerian ducts. Using these novel strains of transgenic mice, the proposed studies will examine the origin and fate of tubularepithelial cells during normal embryonic development and in various pathologic conditions. In the first specific aim, transgenic mice carrying the Ksp-cadherin promoter and Cre recombinase gene will be crossed with mice carrying a lacZ reporter gene that can be activated by Cre/loxP-mediated recombination. Bitransgenic progeny will be stained with X-gal, and the structures that are derived from the mesonephros, metanephros, ureteric bud, and Wolffian and Mullerian ducts will be identified. The second aim will examine the fate of tubular epithelial cells in mice with renal ischemic injury and urinary tract obstruction. Studies will determine whether transdifferentiation of tubular epithelial cells contributes to renal fibrosis and whether surviving mature renal epithelial cells "dedifferentiate" after tubular injury. In the third aim, the origins of renal tubular epithelial cells will be examined using multipotent stem cells in which the Ksp-cadherin promoter directs expression of a GFP reporter gene. Transgenic stem cells will be transplanted into mice with renal ischemic injury, and the expression of GFP will be monitored as an indicator of tubular epithelial differentiation. Collectively, these studies will provide new insights into epithelial differentiation in the kidney and GU tract and the pathogenesis and treatment of important clinical disorders such as congenital kidney abnormalities, intersex, renal interstitial fibrosis, urinary tract obstruction, and acute renal failure.